Cleavage of the plasma membrane Na+/Ca2+ exchanger in excitotoxicity.
摘要：
In brain ischemia, gating of postsynaptic glutamate receptors and other membrane channels triggers intracellular Ca 2+ overload and cell death. In excitotoxic settings, the initial Ca 2+ influx through glutamate receptors is followed by a second uncontrolled Ca 2+ increase that leads to neuronal demise. Here we report that the major plasma membrane Ca 2+ extruding system, the Na +/Ca 2+ exchanger (NCX), is cleaved during brain ischemia and in neurons undergoing excitotoxicity. Inhibition of Ca 2+-activated proteases (calpains) by overexpressing their endogenous inhibitor protein, calpastatin or the expression of an NCX isoform not cleaved by calpains, prevented Ca 2+ overload and rescued neurons from excitotoxic death. Conversely, down-regulation of NCX by siRNA compromised neuronal Ca 2+ handling, transforming the Ca 2+ transient elicited by non-excitotoxic glutamate concentrations into a lethal Ca 2+overload. Thus, proteolytic inactivation of NCX-driven neuronal Ca 2+ extrusion is responsible for the delayed excitotoxic Ca 2+ deregulation and neuronal death.
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DOI：
10.1016/j.cell.2004.11.049
被引量：
年份：
2005
Elsevier
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掌桥科研
Semantic Scholar
万方医学
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